Decreased insulin action, impaired insulin secretion and increased adiposity are important risk factors for development of type 2 diabetes. These risk factors are present even when individuals have both normal fasting and two hour glucose concentrations indicating a very early role for decreased insulin secretion in the development of type 2 diabetes. [unreadable] [unreadable] How increased adiposity leads to decreased insulin action is not clear, but has been investigated in several ways:[unreadable] [unreadable] While increased adiposity itself is a risk factor for type 2 diabetes, individuals with larger fat cells have increased risk of diabetes even after accounting for adiposity. It has been hypothesized that those with larger fat cells are unable to store triglyceride as fat, which is then shunted to other organs. In order to test this hypothesis, fat cell size, adiponectin concentration, visceral, liver and muscle fat and insulin action were measured in obese individuals. Greater fat cell size was associated with increased liver and visceral fat but not increased fat in muscle. Only liver fat was an independent predictor of insulin action indicating that increased it is increased liver fat that mediates the decline in insulin action associated with fat cell size, lower adiponectin concentrations, and increased visceral fat. This implicates the liver as a crucial link between adiposity and insulin action. [unreadable] [unreadable] In addition, different fat depots (subcutaneous versus visceral) may have different effects on insulin action as well. Increases in both visceral and subcutaneous fat depots predict worsening insulin action. But the effect of adiposity differs by sex, with superficial subcutaneous fat being a more important predictor in women, while deep subcutaneous tissue accounts for the largest variance in insulin action in men.[unreadable] [unreadable] Adiposity is also a pro-inflammatory state and such inflammation may affect insulin action directly. We investigated the role of recently identified adipose tissue macrophages and their associations with obesity and insulin action. Adipose tissue macrophages increased with adiposity, and were negatively associated with insulin action, although not independent of adiposity. However, markers of macrophage activation in adipose tissue (specifically plasminogen activator inhibitor-1 (PAI-1) were associated worsening insulin action independent of body fat, indicating a role for macrophage activation in insulin resistance. [unreadable] [unreadable] Factors associated with insulin secretion (another important risk factor for type 2 diabetes) were also investigated. Thyroid hormones, specifically free T3, were positively associated with insulin secretion indicating a role for the thyroid in beta cell function. To investigate additional factors which control insulin secretion, individuals who are undergoing either Roux-en-Y gastric bypass surgery or laporoscopic band will undergo measures of insulin action and insulin secretion prior to and one month following the surgery. This study will investigate how by-pass of the duodenum influences insulin action and secretion.[unreadable] [unreadable] [unreadable] Previous predictors of weight gain based on this study have included, higher respiratory quotient, higher insulin mediated glucose uptake, lower free T3, and relatively lower energy expenditure. Variance in adiposity within the Pima Indian population is largely due to genetic varation as well. Melanocortin 4 receptor variants are the most common monogenetic cause of obesity. Functional melanocortin 4 receptor variants have been identified in the Pima Indian population, including a novel variant predicting a STOP codon. These variants are associated with increased adiposity, but also with lower energy expenditure. This is the first demonstration of an association between a monogenic form of obesity and lower metabolic rate in humans.